- Email: [email protected]
Clinical Significance of Incidentally Detected Aneurysms of the Membranous Ventricular Septum in Adults by Multidetector Computed Tomography
Clinical Significance of Incidentally Detected Aneurysms of the Membranous Ventricular Septum in Adults by Multidetector Computed Tomography Ja Yeon You, MDa, Eun Ju Chun, MD, PhDa,*, Sang Il Choi, MD, PhDa, Eugene Joe, MDa, Whal Lee, MD, PhDb, Joon-Won Kang, MD, PhDc, Myung-Ki Seo, MDd, Yeonyee E. Yoon, MDe, Il-Young Oh, MDe, Eunhee Kim, MDa, and Tae-Hwan Lim, MD, PhDc Although the clinical relevance of aneurysm of the membranous ventricular septum (AMVS) in adults is unclear, the frequency of AMVS detection has been increased because cardiac multidetector computed tomography has been widely adopted for the evaluation of coronary artery disease. Therefore, we aimed to assess the clinical significance of AMVS in a longitudinal study. In 30,120 adults with suspected coronary artery disease who underwent cardiac multidetector computed tomography in 3 hospitals, 52 patients with AMVS were retrospectively selected. We evaluated the clinical symptoms and electrocardiographic abnormalities (cross-sectional study) and the prevalence of embolic stroke (observational study) during a median 40-month (range 6 to 74 months) observation period. For the assessment of embolic stroke, we excluded 9 patients with other explainable embolic sources. Conduction abnormalities were noted in 13 of 52 adults (25%) with AMVS on electrocardiography and embolic stroke occurred in 6 of 43 patients (14%). The mean age and the prevalence of hypertension were significantly higher in the embolic stroke group than in the event-free group (p <0.05). Thrombi were detected in the 11.6% of AMVS, which was significantly related with embolic stroke (p <0.05). The size and morphology did not change in 15 patients with serial follow-up images. In conclusion, our study suggests that AMVS in adults should not be ignored because AMVS may be related to conduction abnormality or embolic stroke, and it does not spontaneously resolve or diminish in size. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;115:354e359) The clinical relevance of an incidentally detected aneurysm of the membranous ventricular septum (AMVS) in adults is unclear. Although most patients with AMVS are asymptomatic, various complications including cerebral embolism,1e4 cardiac arrhythmias,5e7 right ventricular outflow tract obstruction,8e10 bacterial endocarditis,11 and rupture12,13 may occur. AMVS-related cerebral stroke has been documented in several reports. However, to date, no study has been reported regarding the incidence of AMVS-related embolic events or the natural course of AMVS in adults. Therefore, our aim was to evaluate the clinical significance of incidentally detected AMVS in adults with cardiac multidetector computed tomography (MDCT) in a longitudinal study. Methods A database of electrocardiography (ECG)-gated cardiac MDCT from 3 tertiary general hospitals (Seoul National a Department of Radiology and eDepartment of Internal Medicine and Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggido, Korea; Departments of bRadiology and dInternal Medicine, Seoul National University Hospital, Seoul, Korea; and cDepartment of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea. Manuscript received August 5, 2014; revised manuscript received and accepted November 1, 2014. See page 359 for disclosure information. *Corresponding author: Tel: (82) 031-787-7609; fax: (82) 031-7874011. E-mail address: [email protected] (E.J. Chun).
0002-9149/14/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.11.010
University Bundang Hospital, Seoul National University Hospital, and Asan Medical Center in Korea) was used for collection of study subjects. In 30,120 adults who underwent cardiac MDCT for the evaluation of coronary artery disease (CAD) from January 2007 to June 2012, we selected 52 adults (29 women; mean age, 54.0 14.2 years) with incidentally detected AMVS using the key words of “ventricular septal aneurysm,” and “aneurysm of membranous interventricular septum” or combination words of “ventricular septum,” “membranous septum,” “aneurysm,” or “outpouching sac” and observed these patients for evaluation of clinical significance during the mean of 40 months. AMVS was defined as an outpouching sac protruding into the right ventricle, located near the membranous portion of the ventricular septum. We evaluated basic demographic data, risk factors, clinical symptoms, and ECG findings in all subjects. During the median 40-month observation period (range 6 to 74 months) for the evaluation of the direct relation between AMVS and embolic stroke, we excluded 9 patients who had other explainable causes for stroke as follows: significant carotid or cerebral artery atherosclerosis (n ¼ 2), other potential cardiogenic embolic sources, such as intraventricular thrombus (n ¼ 1) and atrial fibrillation (n ¼ 3), or paradoxical embolic source such as atrial septal defect (n ¼ 3).14 Among them, 3 patients have combined patent foramen ovale (PFO). PFO was usually diagnosed using echocardiography with intravenous agitated saline injection and Valsalva maneuver. However, in the patients without transthoracic echocardiography (TTE) examination, a channel-like appearance in the www.ajconline.org
Congenital Heart Disease/Clinical Significance of AMVS
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Figure 1. Flow chart of the study design. SNUBH ¼ Seoul National University Bundang Hospital; SNUH ¼ Seoul National University Hospital; AMC ¼ Asan Medical Center.
Figure 2. Measurement of various parameters on cardiac MDCT. The width (double-headed arrow: W) and length (double-headed arrow: L) of the AMVS are measured as the longest diameter perpendicular and parallel to the ventricular septum on the SA view, respectively (A). The height (double-headed arrow: H) of the AMVS is measured as the longest diameter parallel to the ventricular septum on the 4-chamber view (B). The neck diameter of the AMVS (dotted line: N) is measured as its narrowest portion in the axis of the ventricular septum on each SA (A) or 4-chamber (B) views. The distance from the tricuspid valve (doubleheaded arrow: D) is defined as the shortest diameter from the septal leaflet of the tricuspid valve along the axis of the ventricular septum on the 4-chamber view (C).
interatrial septum with shunt on cardiac MDCT was considered as PFO.15 Therefore, 43 patients (24 women; mean age, 52.5 14.5 years) were finally longitudinally observed for the occurrence of embolic events. The study flow chart is summarized in Figure 1. CT examinations were performed using 64-multidetector CT (Brilliance 64; Philips Medical Systems, Best, The Netherlands) with 64 0.625-mm slice collimation, 420-ms gantry rotation time, and 120-kVp tube voltage; dual-source MDCT (Somatom Definition; Siemens Medical Solutions, Forchheim, Germany) with 2 32 0.6-mm slice
collimation, 330-ms gantry rotation time, and 100- to 120kVp tube voltage; or 256-multidetector CT (Brilliance iCT; Philips Medical Systems, Eindhoven, Netherlands) with 128 0.625-mm detector collimation, 270-ms gantry rotation time, and 100- to 120-kVp tube voltage, according to body mass index. ECG-based tube current modulation was performed in all patients. As routine practice, the CT data were processed using 3-dimensional software (Rapidia; INFINITT, Seoul, Korea), and multiple reformations including the short-axis (SA), 2-chamber, and 4-chamber images were generated.
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Figure 3. Classification of the shape of AMVS on cardiac MDCT. The shape of the AMVS is divided to 3 subcategories based on the 4-chamber view as round (A), lobulated (B), or elongated shape (C). The round shape is defined as spherical feature with a smooth margin. The lobulated shape is defined as a clam-like feature with digitated or scalloped margin. The elongated shape is defined as AMVS height 2 times its width.
Raw cardiac MDCT image data sets of the subjects who had incidentally detected AMVS with MDCT from each institution were sent to a core laboratory for analysis. MDCT images were reviewed independently by 2 experienced cardiovascular radiologists using a workstation with specialized software (TeraRecon Inc., San Mateo, California) blinded to clinical information. The size and morphologic characteristics of AMVS were evaluated to determine the related factors for embolic stroke. The width and length of AMVS were measured on the SA view and the height on the 4-chamber view (Figure 2). The greatest dimension among them was defined as the longest diameter of AMVS. The neck diameter of AMVS was defined as the narrowest portion along the ventricular septum on each view. To measure the distance from the tricuspid valve, the shortest diameter was measured from the septal leaflet of the tricuspid valve along the ventricular septum on the 4-chamber view. The shape of the AMVS was classified into 3 types as follows: (1) round, spherical feature with smooth margin; (2) lobulated, clam-like feature with digitated margin; and (3) elongated, the height of the AMVS being 2 times the width (Figure 3). The volume was calculated assuming that the AMVS was an ellipsoid. We also evaluated for the presence of thrombus attached to AMVS. Any filling defect with low attenuation located in AMVS was defined as intra-aneurysmal thrombus. For all parameters, interobserver agreements were checked, and the average value was used for analysis. In 52 patients with incidentally detected AMVS on cardiac MDCT, TTE was performed in 41 patients; the mean time interval between the 2 methods was 15 days (range 0 to 90 days). TTE examinations were performed using ultrasonographic systems (Acuson Sequoia 512; Siemens, Erlangen, Germany; Philips i33 Cardiograph; Philips Medical Systems, Eindhoven, The Netherlands). All images and measurements were acquired from the standard views, according to the guidelines of the American Society of Echocardiography.16 All TTE images and reports transferred to the core laboratory center were reviewed for the presence of AMVS and intra-aneurysmal thrombus on each standard view by 2 experienced cardiologists. During observation periods, the medical records from each hospital or data from Korean National Statistical Office
Table 1 Baseline demographics of adults with aneurysms of the membranous ventricular septum by multidetector computed tomography (N ¼ 52) Age (years), mean SD Female BMI(kg/m2), mean SD Hypertension Diabetes mellitus Dyslipidemia Smoker Family history of CVD Medication of statin Medication of aspirin or anticoagulation drug Atypical chest pain Dyspnea Palpitation Syncope Asymptomatic, but have clinical risk factors ECG findings Right bundle branch block 1st atrioventricular block Atrial fibrillation Left anterior fascicular block Left bundle branch block Normal or no-specific
54.0 14.2 29 (55.8%) 24.34.0 16 (30.8%) 6 (11.5%) 14 (26.9%) 8 (15.4%) 2 (3.8%) 11 (21.2%) 9 (17.3%) 15 (28.8%) 7 (13.5%) 3 (5.8%) 1 (1.9%) 26 (50.0%) 4 3 3 2 1 39
(7.7%) (5.8%) (5.8%) (3.8%) (1.9%) (75.0%)
BMI ¼ body mass index; CVD ¼ cerebrovascular disease; SD ¼ standard deviation.
and National Health Insurance Corporation were obtained for reviewing the occurrence of embolic stroke. Embolic stroke was defined as multiple scattered cerebral infarctions without not only significant steno-occlusion of relevant arteries but also other explainable cause despite an adequate diagnostic evaluation. In our study, transient ischemic attack of unknown cause was included to the embolic stroke.17 Results were confirmed by an attending neurologist based on clinical symptoms or brain imaging. Statistical analyses were performed using SPSS, version 20.0 (SPSS, Chicago, Illinois). A p value <0.05 was considered statistically significant. For comparison of the morphologic characteristics of AMVS between the embolic stroke group and event-free group and detectability of AMVS between MDCT and TTE, the independent t test and
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Figure 4. Embolic stroke occurred in patients with AMVS. Diffusion-weighted MR images (A, B) show multifocal acute infarctions (arrows) at the left occipital lobe in an 85-year-old man with drowsy mentality. His cardiac MDCT axial image (C) and 4-chamber image (D) show lobulated AMVS and focal filling defects (arrows) within it, which is suspected thrombi. MR ¼ magnetic resonance.
Fisher’s exact test were used for continuous variables and categorical variables, separately. Results The baseline demographic and clinical characteristics of the 52 adults with incidentally detected AMVS by cardiac MDCT are listed in Table 1. Among them, ventricular septal defects were identified in 3 patients, and they were all of insignificant size. The mean age was 54 years (range 23 to 85 years); 55.8% were women. Half of the patients with AMVS have various symptoms such as atypical chest pain or dyspnea, whereas the other half were asymptomatic. On ECG, 13 patients (25%) had conduction anomalies such as with right bundle branch block (RBBB) (n ¼ 4), first-degree atrioventricular block (n ¼ 3), and atrial fibrillation (n ¼ 3). However, these findings were not severe enough to require pacemaker insertion. In the patients who underwent TTE (n ¼ 41), 17 patients (41.5%) had a coexisting valve disease: tricuspid regurgitation (n ¼ 8), mitral regurgitation (n ¼ 6), aortic regurgitation (n ¼ 2), and aortic stenosis (n ¼ 1). Most of these patients had trivial or mild-degree disease, except for only 1 patient who had moderate aortic regurgitation. During the median 40-month observation period, embolic strokes occurred in 6 of 43 patients (14%). In the
embolic stroke group, the mean age (64.3 17.8 vs 50.6 13.1 years, p ¼ 0.029) and the prevalence of hypertension (66.7% vs 16.2%, p ¼ 0.020) were significantly higher than those of the event-free group. Morphologic parameters, such as the longest diameter, volume, neck diameter, or shape, were not significantly different between the 2 groups. Intraaneurysmal thrombi were detected in 5 of 43 patients (11.6%) with cardiac MDCT; all these thrombi were detected in AMVS with lobulated shape. The prevalence of intra-aneurysmal thrombus was significantly higher in the embolic stroke group than in the event-free group (50% vs 5.4%, p ¼ 0.014; Figure 4). All patients with intraaneurysmal thrombi were treated with antiplatelet agents. Three of them who had embolic stroke symptom underwent anticoagulant treatment for 2 weeks. In 52 adults with AMVS, 15 patients underwent followup noninvasive imaging (mean 24 months; range 9 to 61 months) such as cardiac MDCT (n ¼ 7) or TTE (n ¼ 9) during the observation period. One patient underwent both MDCT and TTE during follow-up. There was no significant change in the size of the AMVS (mean difference in the longest diameter 0.4 mm; range 2.5 to 1.8 mm) and morphology at the maximum 61-month follow-up. TTE was performed for 41 of 52 patients with incidentally detected AMVS on cardiac MDCT. AMVS was detected by TTE in 29 of 41 patients (70.7%), in any standard view.
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Table 2 Comparison of morphologic findings of aneurysms of the membranous ventricular septum between TTE(þ) /MDCT(þ) and TTE(-)/MDCT(þ) groups (N ¼ 41) TTE(þ)/MDCT(þ) TTE(-)/MDCT(þ) p-value (n ¼ 29) (n ¼ 12) Longest diameter(mm) Volume(cm3) Valve distance(mm) Widest Neck(mm) Shape Round Lobulated Elongated
16.1 1.3 3.4 9.9
4.4 0.9 3.2 3.8
6 (20.7%) 18 (62.1%) 5 (17.2%)
12.6 0.7 3.0 7.8
2.7 0.5 3.2 2.8
3 (25.0%) 7 (58.3%) 2 (16.7%)
.004* .012* .698 .096 .955
* p<.05.
AMVS was most commonly visualized on the SA view (77.8%), whereas poorly visualized on the 2-chamber view (22.2%). TTE did not detect AMVS in 12 patients (29.3%) with MDCT-detected AMVS; this was named the TTE()/ MDCT(þ) AMVS group. The longest dimension and volume of the AMVS were significantly smaller in the TTE()/ MDCT(þ) AMVS group than the TTE(þ)/MDCT(þ) AMVS group (p <0.05; Table 2). In the 12 patients with TTE()/MDCT(þ) AMVS, 5 patients (41.7%) had an AMVS volume <0.5 cm3, which was the most common cause of the undetected AMVS with TTE. Other explanations for AMVS being undetected by TTE were poor sonic window because of cardiac valve calcification (n ¼ 3), calcified apical pseudoaneurysm of the left ventricle (n ¼ 1), obesity with a body mass index >30 kg/m2 (n ¼ 1), and severe thoracic deformity (n ¼ 1). One case was diagnosed as shielded AMVS because of dilated sinus of Valsalva (n ¼ 1). In the TTE()/MDCT(þ) AMVS group, 1 patient had an episode of acute embolic stroke. Although intra-aneurysmal thrombi were detected by MDCT in 5 patients, none of these thrombi were detected by TTE. The reasons for this were poor sonic window (n ¼ 1), anticoagulant therapy on diagnosis with cardiac MDCT (n ¼ 2), and long interval with >5 days between MDCT and TTE (n ¼ 2). Discussion In this study of adults with incidentally detected AMVS by MDCT, we found that 25% of adults with AMVS showed conduction abnormality on ECG and embolic stroke occurred in 14% of AMVS cases during a median 40-month observation period. In addition, AMVS did not change in size or morphology during the maximum 61-month follow-up. Previous studies have shown various conduction abnormalities such as RBBB, ventricular tachycardia, atrial fibrillation, and atrioventricular block in patients with AMVS.5e7,18,19 Although ambulatory Holter monitoring was not performed systematically in our study, evidence of conduction abnormalities such as RBBB and a first-degree atrioventricular block, as shown in patients’ medical and ECG records, was present in 25% of the patients with AMVS; however, these findings were not serious enough to require a pacemaker. AMVS is formed by adherence of the tricuspid septal leaflet tissue13 or by the tissue arising from
the vicinity of the tricuspid valve.20 Therefore, considering the location of the His bundle that originates from the atrioventricular node on the wall of the right atrium around the tricuspid valve and runs along the ventricular septal wall, AMVS may be associated with cardiac conduction abnormality by interfering with the function of the His bundle. Currently, AMVS may be underestimated as a potential source of cardiac embolism in cardiologists because of a lack of information on the prevalence of AMVS-related embolic stroke, although several scattered anecdotal reports have documented the suspicion of an association between AMVS and unexplained stroke.1e4,21,22 In our study, embolic stroke was identified in 14% of the adults with incidentally detected AMVS during the median 40-month follow-up. The incidence may be higher than the actual incidence because we did not perform brain imaging in all patients before the cardiac CT scan; thus, we could not perfectly exclude the previous silent stroke although we excluded well-known potential embolic sources such as intracardiac thrombus or PFO. Nevertheless, our study is the first to report the prevalence of AMVS-related embolic stroke during an observation period >3 years. In a previous study by Choi et al5 that evaluated the clinical features of patients with AMVS confirmed by cardiac MDCT, no embolic event was identified because of the absence of follow-up. However, the idea of AMVS as a cause of embolic stroke should be carefully considered because we only compared the various clinical parameters between the embolic event and event-free groups in patients with AMVS, and no adjustments were made for the risk factors for stroke, such as hypertension or age. In our study, the presence of intra-aneurysmal thrombus was detected in 11.6% of the adults with AMVS using MDCT, which was significantly correlated with embolic stroke. Our results support the idea that AMVS could be a potential source of thrombus formation and are consistent with previous studies regarding the relation between AMVS and embolic stroke.1e4,21,22 Bush et al4 confirmed intra-aneurysmal thrombi in the AMVS by cardiac surgery in patients with embolic stroke. Therefore, further prospective studies with adequate control groups will be necessary not only to define AMVS as a definite independent predictor of embolic stroke but also to determine the therapeutic strategy for AMVS, such as anticoagulation therapy or surgical removal. Although AMVS has been related to the spontaneous closure or decrease in the size of VSDs in infancy and adolescence,23e26 there is a lack of information on the incidence and natural course of AMVS in adults. As far as we know, this is the first report demonstrating the natural course and clinical implication of AMVS in adults through a longitudinal study. Our results showed no changes in the size or morphology of AMVS during a maximum of 61 months, indicating that AMVS may be a semipermanent cardioembolic source in adults rather than in infancy and adolescence. In our study, cardiac MDCT was useful for the detection of AMVS in patients who have a poor sonic window caused by calcifications, thoracic wall deformity, or obesity.27 In addition, MDCT has excellent spatial resolution and the advantage of detailed anatomy with 3-dimentional view;
Congenital Heart Disease/Clinical Significance of AMVS
therefore, MDCT can characterize the AMVS. Another remarkable finding was that intra-aneurysmal thrombi identified by cardiac MDCT were all missed by TTE. A possible explanation is that in our study, all thrombi were found in the AMVS of lobulated shape and distributed along the digitated margin of the AMVS. Hence, TTE did not distinguish the echogenic thrombus from the echogenic lobulated margin because of the limited resolution of TTE. Several previous studies reported that intra-aneurysmal thrombi in AMVS were detected by TTE. However, unlike in our study, in those previous studies, the thrombi were large and compactly filled almost the whole space of the AMVS.2,4 Our study has several limitations. First, we did not estimate the real incidence of AMVS and the exact frequency of clinical events in the general population because this retrospective study was performed at a tertiary medical center with highly selective patients. Nevertheless, our study supports the considerable link between AMVS and clinical events including potential cardiogenic embolic infarction and conduction abnormality. Second, TTE was not performed in all patients with AMVS detected by cardiac MDCT. Therefore, false-positive or false-negative values of cardiac MDCT for AMVS or intra-aneurysmal thrombus may not be explained in our study. Finally, we did not prove whether the thrombi detected by cardiac MDCT truly existed using TTE or through surgical assessment. However, cardiac MDCT is also considered as a potentially noninvasive and efficacious method for identification of intracardiac thrombi with acceptable reliability and advanced temporal and spatial resolution.28 Disclosures This work was supported by the National Research Foundation grant NRF-2010-0023504 funded by the Korea government (MEST). 1. Fabijanic D, Bulat C, Batinic T, Carevic V, Caljkusic K. Membranous ventricular septum aneurysm as a cause of recurrent transient ischemic attack. J Cardiovasc Ultrasound 2012;20:114e115. 2. Salazar J, Gutierrez A, Cay E, Ballester C, Salazar JJ, Placer L. Cerebral embolism and thrombus in a membranous interventricular septal aneurysm. Ann Thorac Surg 2003;76:286e287. 3. Lin JM, Hwang JJ, Chiu IS. Cerebral embolism from the thrombus in the atrioventricular septal aneurysm. Cardiology 1995;86:441e443. 4. Bush HS, Perin E, Massumi A, Klima T, Hall RJ. Detection of thrombus in an aneurysm of the ventricular septum. Am J Cardiol 1989;63:1533e1535. 5. Choi M, Jung JI, Lee BY, Kim HR. Ventricular septal aneurysms in adults: findings of cardiac CT images and correlation with clinical features. Acta Radiol 2011;52:619e623. 6. Jang SW, Rho TH, Kim JH. Membranous interventricular septal aneurysm resulted in complete atrioventricular block. Heart 2010;96:244. 7. Heggtveit HA. Congenital aneurysm of the membranous septum associated with bundle branch block. Am J Cardiol 1964;14:112e117. 8. Chen SY, Chan KL, Beauchesne LM. Right ventricular outflow tract obstruction secondary to a membranous ventricular septal aneurysm. Eur J Echocardiogr 2011;12:886. 9. Sharma A, Kern MJ, Callicoat P, Aguirre F, Labovitz A, Willman VL. Severe subpulmonic outflow obstruction caused by aneurysm of the membranous ventricular septum: diagnosis by transesophageal echocardiography. Am Heart J 1992;123:810e814.
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10. Falsetti HL, Andersen MN. Aneurysm of the membranous ventricular septum producing right ventricular outflow tract obstruction and left ventricular failure. Chest 1971;59:578e580. 11. Walpot J, Peerenboom P, van Wylick A, Klazen C. Aneurysm of the membranous septum with ventricular septal defect and infective endocarditis. Eur J Echocardiogr 2004;5:391e393. 12. Loukas M, Tubbs RS, Louis RG Jr, Curry B. Pseudoaneurysm of the membranous septum, case report and review of the literature. Surg Radiol Anat 2006;28:564e568. 13. Yilmaz AT, Ozal E, Arslan M, Tatar H, Ozturk OY. Aneurysm of the membranous septum in adult patients with perimembranous ventricular septal defect. Eur J Cardiothorac Surg 1997;11:307e311. 14. Jin KN, Chun EJ, Choi SI, Ko SM, Han M-K, Bae H-J, Park JH. Cardioembolic origin in patients with embolic stroke: spectrum of imaging findings on cardiac MDCT. Am J Roentgenol 2010;195: W38eW44. 15. Saremi F, Channual S, Raney A, Gurudevan SV, Narula J, Fowler S, Abolhoda A, Milliken JC. Imaging of patent foramen ovale with 64-section multidetector CT. Radiology 2008;249:483e492. 16. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440e1463. 17. Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, Hatsukami TS, Higashida RT, Johnston SC, Kidwell CS. Definition and evaluation of transient ischemic attack a Scientific statement for Healthcare Professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease: the American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke 2009;40:2276e2293. 18. Santamaria M, Cireddu M, Riva S, Trevisi N, Della Bella P. Radiofrequency catheter ablation guided by noncontact mapping of ventricular tachycardia originating from an idiopathic left ventricular aneurysm. J Interv Card Electrophysiol 2007;19:49e53. 19. Graffigna A, Minzioni G, Ressia L, Vigano M. Surgical ablation of ventricular tachycardia secondary to congenital ventricular septal aneurysm. Ann Thorac Surg 1994;57:921e924. 20. Anderson RH, Lenox CC, Zuberbuhler JR. Mechanisms of closure of perimembranous ventricular septal defect. Am J Cardiol 1983;52: 341e345. 21. Langer C, Horstkotte D, Piper C. Aneurysm of the membranous septum causes pre-syncopes and transient bilateral blindness. Eur Heart J 2007;28:784. 22. Thomas D, Salloum J, Rancurel G. Aneurysm of the interventricular membranous septum with thrombo-embolism—an indication for surgical repair? Eur Heart J 1993;14:1717e1718. 23. Miyake T, Shinohara T, Nakamura Y, Fukuda T, Tasato H, Toyohara K, Tanihira Y. Aneurysm of the ventricular membranous septum: serial echocardiographic studies. Pediatr Cardiol 2004;25:585e589. 24. Ramaciotti C, Keren A, Silverman NH. Importance of (perimembranous) ventricular septal aneurysm in the natural history of isolated perimembranous ventricular septal defect. Am J Cardiol 1986;57: 268e272. 25. Alpert BS, Cook DH, Varghese PJ, Rowe RD. Spontaneous closure of small ventricular septal defects: ten-year follow-up. Pediatrics 1979;63:204e206. 26. Varghese PJ, Izukawa T, Celermajer J, Simon A, Rowe RD. Aneurysm of the membranous ventricular septum. A method of spontaneous closure of small ventricular septal defect. Am J Cardiol 1969;24: 531e536. 27. Khalid O, Koenig P. The use of echocardiography in congenital heart surgery and intervention. Exp Rev Cardiovasc Ther 2006;4:263e271. 28. Wu X, Wang C, Zhang C, Zhang Y, Ding F, Yan J. Computed tomography for detecting left atrial thrombus: a meta-analysis. Arch Med Sci 2012;8:943e951.
0002-9149/14/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.11.010
University Bundang Hospital, Seoul National University Hospital, and Asan Medical Center in Korea) was used for collection of study subjects. In 30,120 adults who underwent cardiac MDCT for the evaluation of coronary artery disease (CAD) from January 2007 to June 2012, we selected 52 adults (29 women; mean age, 54.0 14.2 years) with incidentally detected AMVS using the key words of “ventricular septal aneurysm,” and “aneurysm of membranous interventricular septum” or combination words of “ventricular septum,” “membranous septum,” “aneurysm,” or “outpouching sac” and observed these patients for evaluation of clinical significance during the mean of 40 months. AMVS was defined as an outpouching sac protruding into the right ventricle, located near the membranous portion of the ventricular septum. We evaluated basic demographic data, risk factors, clinical symptoms, and ECG findings in all subjects. During the median 40-month observation period (range 6 to 74 months) for the evaluation of the direct relation between AMVS and embolic stroke, we excluded 9 patients who had other explainable causes for stroke as follows: significant carotid or cerebral artery atherosclerosis (n ¼ 2), other potential cardiogenic embolic sources, such as intraventricular thrombus (n ¼ 1) and atrial fibrillation (n ¼ 3), or paradoxical embolic source such as atrial septal defect (n ¼ 3).14 Among them, 3 patients have combined patent foramen ovale (PFO). PFO was usually diagnosed using echocardiography with intravenous agitated saline injection and Valsalva maneuver. However, in the patients without transthoracic echocardiography (TTE) examination, a channel-like appearance in the www.ajconline.org
Congenital Heart Disease/Clinical Significance of AMVS
355
Figure 1. Flow chart of the study design. SNUBH ¼ Seoul National University Bundang Hospital; SNUH ¼ Seoul National University Hospital; AMC ¼ Asan Medical Center.
Figure 2. Measurement of various parameters on cardiac MDCT. The width (double-headed arrow: W) and length (double-headed arrow: L) of the AMVS are measured as the longest diameter perpendicular and parallel to the ventricular septum on the SA view, respectively (A). The height (double-headed arrow: H) of the AMVS is measured as the longest diameter parallel to the ventricular septum on the 4-chamber view (B). The neck diameter of the AMVS (dotted line: N) is measured as its narrowest portion in the axis of the ventricular septum on each SA (A) or 4-chamber (B) views. The distance from the tricuspid valve (doubleheaded arrow: D) is defined as the shortest diameter from the septal leaflet of the tricuspid valve along the axis of the ventricular septum on the 4-chamber view (C).
interatrial septum with shunt on cardiac MDCT was considered as PFO.15 Therefore, 43 patients (24 women; mean age, 52.5 14.5 years) were finally longitudinally observed for the occurrence of embolic events. The study flow chart is summarized in Figure 1. CT examinations were performed using 64-multidetector CT (Brilliance 64; Philips Medical Systems, Best, The Netherlands) with 64 0.625-mm slice collimation, 420-ms gantry rotation time, and 120-kVp tube voltage; dual-source MDCT (Somatom Definition; Siemens Medical Solutions, Forchheim, Germany) with 2 32 0.6-mm slice
collimation, 330-ms gantry rotation time, and 100- to 120kVp tube voltage; or 256-multidetector CT (Brilliance iCT; Philips Medical Systems, Eindhoven, Netherlands) with 128 0.625-mm detector collimation, 270-ms gantry rotation time, and 100- to 120-kVp tube voltage, according to body mass index. ECG-based tube current modulation was performed in all patients. As routine practice, the CT data were processed using 3-dimensional software (Rapidia; INFINITT, Seoul, Korea), and multiple reformations including the short-axis (SA), 2-chamber, and 4-chamber images were generated.
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Figure 3. Classification of the shape of AMVS on cardiac MDCT. The shape of the AMVS is divided to 3 subcategories based on the 4-chamber view as round (A), lobulated (B), or elongated shape (C). The round shape is defined as spherical feature with a smooth margin. The lobulated shape is defined as a clam-like feature with digitated or scalloped margin. The elongated shape is defined as AMVS height 2 times its width.
Raw cardiac MDCT image data sets of the subjects who had incidentally detected AMVS with MDCT from each institution were sent to a core laboratory for analysis. MDCT images were reviewed independently by 2 experienced cardiovascular radiologists using a workstation with specialized software (TeraRecon Inc., San Mateo, California) blinded to clinical information. The size and morphologic characteristics of AMVS were evaluated to determine the related factors for embolic stroke. The width and length of AMVS were measured on the SA view and the height on the 4-chamber view (Figure 2). The greatest dimension among them was defined as the longest diameter of AMVS. The neck diameter of AMVS was defined as the narrowest portion along the ventricular septum on each view. To measure the distance from the tricuspid valve, the shortest diameter was measured from the septal leaflet of the tricuspid valve along the ventricular septum on the 4-chamber view. The shape of the AMVS was classified into 3 types as follows: (1) round, spherical feature with smooth margin; (2) lobulated, clam-like feature with digitated margin; and (3) elongated, the height of the AMVS being 2 times the width (Figure 3). The volume was calculated assuming that the AMVS was an ellipsoid. We also evaluated for the presence of thrombus attached to AMVS. Any filling defect with low attenuation located in AMVS was defined as intra-aneurysmal thrombus. For all parameters, interobserver agreements were checked, and the average value was used for analysis. In 52 patients with incidentally detected AMVS on cardiac MDCT, TTE was performed in 41 patients; the mean time interval between the 2 methods was 15 days (range 0 to 90 days). TTE examinations were performed using ultrasonographic systems (Acuson Sequoia 512; Siemens, Erlangen, Germany; Philips i33 Cardiograph; Philips Medical Systems, Eindhoven, The Netherlands). All images and measurements were acquired from the standard views, according to the guidelines of the American Society of Echocardiography.16 All TTE images and reports transferred to the core laboratory center were reviewed for the presence of AMVS and intra-aneurysmal thrombus on each standard view by 2 experienced cardiologists. During observation periods, the medical records from each hospital or data from Korean National Statistical Office
Table 1 Baseline demographics of adults with aneurysms of the membranous ventricular septum by multidetector computed tomography (N ¼ 52) Age (years), mean SD Female BMI(kg/m2), mean SD Hypertension Diabetes mellitus Dyslipidemia Smoker Family history of CVD Medication of statin Medication of aspirin or anticoagulation drug Atypical chest pain Dyspnea Palpitation Syncope Asymptomatic, but have clinical risk factors ECG findings Right bundle branch block 1st atrioventricular block Atrial fibrillation Left anterior fascicular block Left bundle branch block Normal or no-specific
54.0 14.2 29 (55.8%) 24.34.0 16 (30.8%) 6 (11.5%) 14 (26.9%) 8 (15.4%) 2 (3.8%) 11 (21.2%) 9 (17.3%) 15 (28.8%) 7 (13.5%) 3 (5.8%) 1 (1.9%) 26 (50.0%) 4 3 3 2 1 39
(7.7%) (5.8%) (5.8%) (3.8%) (1.9%) (75.0%)
BMI ¼ body mass index; CVD ¼ cerebrovascular disease; SD ¼ standard deviation.
and National Health Insurance Corporation were obtained for reviewing the occurrence of embolic stroke. Embolic stroke was defined as multiple scattered cerebral infarctions without not only significant steno-occlusion of relevant arteries but also other explainable cause despite an adequate diagnostic evaluation. In our study, transient ischemic attack of unknown cause was included to the embolic stroke.17 Results were confirmed by an attending neurologist based on clinical symptoms or brain imaging. Statistical analyses were performed using SPSS, version 20.0 (SPSS, Chicago, Illinois). A p value <0.05 was considered statistically significant. For comparison of the morphologic characteristics of AMVS between the embolic stroke group and event-free group and detectability of AMVS between MDCT and TTE, the independent t test and
Congenital Heart Disease/Clinical Significance of AMVS
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Figure 4. Embolic stroke occurred in patients with AMVS. Diffusion-weighted MR images (A, B) show multifocal acute infarctions (arrows) at the left occipital lobe in an 85-year-old man with drowsy mentality. His cardiac MDCT axial image (C) and 4-chamber image (D) show lobulated AMVS and focal filling defects (arrows) within it, which is suspected thrombi. MR ¼ magnetic resonance.
Fisher’s exact test were used for continuous variables and categorical variables, separately. Results The baseline demographic and clinical characteristics of the 52 adults with incidentally detected AMVS by cardiac MDCT are listed in Table 1. Among them, ventricular septal defects were identified in 3 patients, and they were all of insignificant size. The mean age was 54 years (range 23 to 85 years); 55.8% were women. Half of the patients with AMVS have various symptoms such as atypical chest pain or dyspnea, whereas the other half were asymptomatic. On ECG, 13 patients (25%) had conduction anomalies such as with right bundle branch block (RBBB) (n ¼ 4), first-degree atrioventricular block (n ¼ 3), and atrial fibrillation (n ¼ 3). However, these findings were not severe enough to require pacemaker insertion. In the patients who underwent TTE (n ¼ 41), 17 patients (41.5%) had a coexisting valve disease: tricuspid regurgitation (n ¼ 8), mitral regurgitation (n ¼ 6), aortic regurgitation (n ¼ 2), and aortic stenosis (n ¼ 1). Most of these patients had trivial or mild-degree disease, except for only 1 patient who had moderate aortic regurgitation. During the median 40-month observation period, embolic strokes occurred in 6 of 43 patients (14%). In the
embolic stroke group, the mean age (64.3 17.8 vs 50.6 13.1 years, p ¼ 0.029) and the prevalence of hypertension (66.7% vs 16.2%, p ¼ 0.020) were significantly higher than those of the event-free group. Morphologic parameters, such as the longest diameter, volume, neck diameter, or shape, were not significantly different between the 2 groups. Intraaneurysmal thrombi were detected in 5 of 43 patients (11.6%) with cardiac MDCT; all these thrombi were detected in AMVS with lobulated shape. The prevalence of intra-aneurysmal thrombus was significantly higher in the embolic stroke group than in the event-free group (50% vs 5.4%, p ¼ 0.014; Figure 4). All patients with intraaneurysmal thrombi were treated with antiplatelet agents. Three of them who had embolic stroke symptom underwent anticoagulant treatment for 2 weeks. In 52 adults with AMVS, 15 patients underwent followup noninvasive imaging (mean 24 months; range 9 to 61 months) such as cardiac MDCT (n ¼ 7) or TTE (n ¼ 9) during the observation period. One patient underwent both MDCT and TTE during follow-up. There was no significant change in the size of the AMVS (mean difference in the longest diameter 0.4 mm; range 2.5 to 1.8 mm) and morphology at the maximum 61-month follow-up. TTE was performed for 41 of 52 patients with incidentally detected AMVS on cardiac MDCT. AMVS was detected by TTE in 29 of 41 patients (70.7%), in any standard view.
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Table 2 Comparison of morphologic findings of aneurysms of the membranous ventricular septum between TTE(þ) /MDCT(þ) and TTE(-)/MDCT(þ) groups (N ¼ 41) TTE(þ)/MDCT(þ) TTE(-)/MDCT(þ) p-value (n ¼ 29) (n ¼ 12) Longest diameter(mm) Volume(cm3) Valve distance(mm) Widest Neck(mm) Shape Round Lobulated Elongated
16.1 1.3 3.4 9.9
4.4 0.9 3.2 3.8
6 (20.7%) 18 (62.1%) 5 (17.2%)
12.6 0.7 3.0 7.8
2.7 0.5 3.2 2.8
3 (25.0%) 7 (58.3%) 2 (16.7%)
.004* .012* .698 .096 .955
* p<.05.
AMVS was most commonly visualized on the SA view (77.8%), whereas poorly visualized on the 2-chamber view (22.2%). TTE did not detect AMVS in 12 patients (29.3%) with MDCT-detected AMVS; this was named the TTE()/ MDCT(þ) AMVS group. The longest dimension and volume of the AMVS were significantly smaller in the TTE()/ MDCT(þ) AMVS group than the TTE(þ)/MDCT(þ) AMVS group (p <0.05; Table 2). In the 12 patients with TTE()/MDCT(þ) AMVS, 5 patients (41.7%) had an AMVS volume <0.5 cm3, which was the most common cause of the undetected AMVS with TTE. Other explanations for AMVS being undetected by TTE were poor sonic window because of cardiac valve calcification (n ¼ 3), calcified apical pseudoaneurysm of the left ventricle (n ¼ 1), obesity with a body mass index >30 kg/m2 (n ¼ 1), and severe thoracic deformity (n ¼ 1). One case was diagnosed as shielded AMVS because of dilated sinus of Valsalva (n ¼ 1). In the TTE()/MDCT(þ) AMVS group, 1 patient had an episode of acute embolic stroke. Although intra-aneurysmal thrombi were detected by MDCT in 5 patients, none of these thrombi were detected by TTE. The reasons for this were poor sonic window (n ¼ 1), anticoagulant therapy on diagnosis with cardiac MDCT (n ¼ 2), and long interval with >5 days between MDCT and TTE (n ¼ 2). Discussion In this study of adults with incidentally detected AMVS by MDCT, we found that 25% of adults with AMVS showed conduction abnormality on ECG and embolic stroke occurred in 14% of AMVS cases during a median 40-month observation period. In addition, AMVS did not change in size or morphology during the maximum 61-month follow-up. Previous studies have shown various conduction abnormalities such as RBBB, ventricular tachycardia, atrial fibrillation, and atrioventricular block in patients with AMVS.5e7,18,19 Although ambulatory Holter monitoring was not performed systematically in our study, evidence of conduction abnormalities such as RBBB and a first-degree atrioventricular block, as shown in patients’ medical and ECG records, was present in 25% of the patients with AMVS; however, these findings were not serious enough to require a pacemaker. AMVS is formed by adherence of the tricuspid septal leaflet tissue13 or by the tissue arising from
the vicinity of the tricuspid valve.20 Therefore, considering the location of the His bundle that originates from the atrioventricular node on the wall of the right atrium around the tricuspid valve and runs along the ventricular septal wall, AMVS may be associated with cardiac conduction abnormality by interfering with the function of the His bundle. Currently, AMVS may be underestimated as a potential source of cardiac embolism in cardiologists because of a lack of information on the prevalence of AMVS-related embolic stroke, although several scattered anecdotal reports have documented the suspicion of an association between AMVS and unexplained stroke.1e4,21,22 In our study, embolic stroke was identified in 14% of the adults with incidentally detected AMVS during the median 40-month follow-up. The incidence may be higher than the actual incidence because we did not perform brain imaging in all patients before the cardiac CT scan; thus, we could not perfectly exclude the previous silent stroke although we excluded well-known potential embolic sources such as intracardiac thrombus or PFO. Nevertheless, our study is the first to report the prevalence of AMVS-related embolic stroke during an observation period >3 years. In a previous study by Choi et al5 that evaluated the clinical features of patients with AMVS confirmed by cardiac MDCT, no embolic event was identified because of the absence of follow-up. However, the idea of AMVS as a cause of embolic stroke should be carefully considered because we only compared the various clinical parameters between the embolic event and event-free groups in patients with AMVS, and no adjustments were made for the risk factors for stroke, such as hypertension or age. In our study, the presence of intra-aneurysmal thrombus was detected in 11.6% of the adults with AMVS using MDCT, which was significantly correlated with embolic stroke. Our results support the idea that AMVS could be a potential source of thrombus formation and are consistent with previous studies regarding the relation between AMVS and embolic stroke.1e4,21,22 Bush et al4 confirmed intra-aneurysmal thrombi in the AMVS by cardiac surgery in patients with embolic stroke. Therefore, further prospective studies with adequate control groups will be necessary not only to define AMVS as a definite independent predictor of embolic stroke but also to determine the therapeutic strategy for AMVS, such as anticoagulation therapy or surgical removal. Although AMVS has been related to the spontaneous closure or decrease in the size of VSDs in infancy and adolescence,23e26 there is a lack of information on the incidence and natural course of AMVS in adults. As far as we know, this is the first report demonstrating the natural course and clinical implication of AMVS in adults through a longitudinal study. Our results showed no changes in the size or morphology of AMVS during a maximum of 61 months, indicating that AMVS may be a semipermanent cardioembolic source in adults rather than in infancy and adolescence. In our study, cardiac MDCT was useful for the detection of AMVS in patients who have a poor sonic window caused by calcifications, thoracic wall deformity, or obesity.27 In addition, MDCT has excellent spatial resolution and the advantage of detailed anatomy with 3-dimentional view;
Congenital Heart Disease/Clinical Significance of AMVS
therefore, MDCT can characterize the AMVS. Another remarkable finding was that intra-aneurysmal thrombi identified by cardiac MDCT were all missed by TTE. A possible explanation is that in our study, all thrombi were found in the AMVS of lobulated shape and distributed along the digitated margin of the AMVS. Hence, TTE did not distinguish the echogenic thrombus from the echogenic lobulated margin because of the limited resolution of TTE. Several previous studies reported that intra-aneurysmal thrombi in AMVS were detected by TTE. However, unlike in our study, in those previous studies, the thrombi were large and compactly filled almost the whole space of the AMVS.2,4 Our study has several limitations. First, we did not estimate the real incidence of AMVS and the exact frequency of clinical events in the general population because this retrospective study was performed at a tertiary medical center with highly selective patients. Nevertheless, our study supports the considerable link between AMVS and clinical events including potential cardiogenic embolic infarction and conduction abnormality. Second, TTE was not performed in all patients with AMVS detected by cardiac MDCT. Therefore, false-positive or false-negative values of cardiac MDCT for AMVS or intra-aneurysmal thrombus may not be explained in our study. Finally, we did not prove whether the thrombi detected by cardiac MDCT truly existed using TTE or through surgical assessment. However, cardiac MDCT is also considered as a potentially noninvasive and efficacious method for identification of intracardiac thrombi with acceptable reliability and advanced temporal and spatial resolution.28 Disclosures This work was supported by the National Research Foundation grant NRF-2010-0023504 funded by the Korea government (MEST). 1. Fabijanic D, Bulat C, Batinic T, Carevic V, Caljkusic K. Membranous ventricular septum aneurysm as a cause of recurrent transient ischemic attack. J Cardiovasc Ultrasound 2012;20:114e115. 2. Salazar J, Gutierrez A, Cay E, Ballester C, Salazar JJ, Placer L. Cerebral embolism and thrombus in a membranous interventricular septal aneurysm. Ann Thorac Surg 2003;76:286e287. 3. Lin JM, Hwang JJ, Chiu IS. Cerebral embolism from the thrombus in the atrioventricular septal aneurysm. Cardiology 1995;86:441e443. 4. Bush HS, Perin E, Massumi A, Klima T, Hall RJ. Detection of thrombus in an aneurysm of the ventricular septum. Am J Cardiol 1989;63:1533e1535. 5. Choi M, Jung JI, Lee BY, Kim HR. Ventricular septal aneurysms in adults: findings of cardiac CT images and correlation with clinical features. Acta Radiol 2011;52:619e623. 6. Jang SW, Rho TH, Kim JH. Membranous interventricular septal aneurysm resulted in complete atrioventricular block. Heart 2010;96:244. 7. Heggtveit HA. Congenital aneurysm of the membranous septum associated with bundle branch block. Am J Cardiol 1964;14:112e117. 8. Chen SY, Chan KL, Beauchesne LM. Right ventricular outflow tract obstruction secondary to a membranous ventricular septal aneurysm. Eur J Echocardiogr 2011;12:886. 9. Sharma A, Kern MJ, Callicoat P, Aguirre F, Labovitz A, Willman VL. Severe subpulmonic outflow obstruction caused by aneurysm of the membranous ventricular septum: diagnosis by transesophageal echocardiography. Am Heart J 1992;123:810e814.
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